IMS III is an international multi-center, open-label, randomized Phase III Trial with a maximum of 900 subjects. The trial will determine if subjects with an NIHSSS 10 at baseline, or NIHSSS of 8-9 with major arterial occlusion by CTA, treated with a combined approach to recanalization started within 3 hours of onset are more likely to have a favorable outcome at 3 months (mRS 0-2) as compared to subjects treated with standard IV rt-PA alone. The trial is designed to test the hypothesis that there is an overall absolute difference of at least 10% in the proportion of a favorable outcome for subjects treated with the combined approach overall as compared to those treated with the standard dose of IV rt-PA. Subjects are randomized in a 2:1 ratio with more subjects assigned to the combined approach group. The trial is open-label since blinding of the intervention is not possible, but the primary 3-month and secondary endpoints are done by an investigator blinded as to treatment assignment. Additional endpoints include: (1) other outcome measures used in the NINDS rt-PA Stroke Trial (Barthel Index, NIHSS, the Trailmaking test Parts A and B, and the EuroQol EQ-5D at 3 months; (2) early response to treatment as determined by an NIHSSS of 0-2 at 24 hours; (3) a CT angiography assessment of intracranial vascular patency at 24 hours; (4) the volume of infarction on 24-hour CT; (5) the rate of reperfusion (TICI Grade II or III perfusion flow) and the rate of AOL (arterial occlusive lesion) Grade II or III recanalization at completion of angiography (combined approach group only); and (6) economic outcomes (resource utilization) at 3, 6, 9 and 12 months. The Trial currently is supported by two NINDS cooperative agreement grants: (1) to the University of Cincinnati Clinical Coordinating and Angiographic Imaging Center (PI: Joseph P. Broderick, MD) to provide clinical leadership and project and site management; and (2) to the Statistical and Data Coordinating Center (SDCC) at the Medical University of South Carolina (PI: Yuko Y. Palesch, PhD) to provide data management and statistical expertise. The primary goal of this competitive renewal is to complete enrollment into the trial with data quality of the highest standard by ongoing aggressive recruitment strategies as well as by expansion of the trial to Europe and additional sites. The trial design continues to emphasize the importance of minimizing the time from stroke onset to start of IV and lA therapy.